- The study investigated glycoprotein nonmetastatic melanoma B (GPNMB)'s role in alpha-synuclein pathology in Parkinson's disease.
- Researchers used induced pluripotent stem cell-derived microglia and examined 1,675 human postmortem brains.
- GPNMB genotypes conferring higher expression were associated with more widespread alpha-synuclein pathology in human brains.
- The authors concluded that microglial GPNMB secretion forms a positive feedback loop, enhancing neuronal alpha-synuclein pathology.
- Anti-GPNMB antibodies therapeutically interrupt this cycle, suggesting a potential strategy for Parkinson's disease.
Unraveling Alpha-Synuclein Propagation in Parkinson's Disease
Developing therapies that halt or slow the progression of Parkinson's disease (PD) remains a central challenge, largely because the mechanisms driving the spread of pathology are not fully understood [1, 2]. The disease is defined by the progressive loss of dopaminergic neurons and the accumulation of aggregated alpha-synuclein in Lewy bodies [1, 3, 4]. A key area of investigation is the cell-to-cell transmission of these pathological protein aggregates, which contributes to widespread neurodegeneration [5, 6]. Microglia, the resident immune cells of the central nervous system, are known to be deeply involved in this process. They can play a dual role, either clearing protein aggregates or promoting neuroinflammatory responses that worsen neuronal damage [7, 8, 9, 10]. A recent study now provides a more detailed molecular map of how microglia may actively facilitate the propagation of alpha-synuclein pathology.
GPNMB's Role in Alpha-Synuclein Uptake and Pathology
The investigation centers on Glycoprotein nonmetastatic melanoma B (GPNMB), a protein the study identifies as critical to the cellular uptake of pathological forms of alpha-synuclein. The researchers established that the extracellular domain of GPNMB, which is not anchored to a cell membrane, can function in a non-cell-autonomous manner. This means the protein can be secreted by one cell and subsequently influence the behavior of other nearby cells, providing a potential vehicle for intercellular communication and pathology transfer. In the human brain, GPNMB is expressed in both neurons and microglia, placing it at the crossroads of the neurodegenerative process. The ability of secreted GPNMB to act on neighboring cells suggests a mechanism by which it could mediate the spread of alpha-synuclein pathology beyond the immediate vicinity of the cell that produced it.
Microglial Secretion of GPNMB Amplifies Neuronal Alpha-Synuclein Pathology
To clarify the role of microglia in this pathway, the researchers used induced pluripotent stem cell-derived microglia (iMicroglia), which are human microglia grown in a laboratory setting to model cellular interactions. They found that when these iMicroglia were exposed to apoptotic, or dying, neurons, their expression and subsequent secretion of GPNMB significantly increased. This observation points to a potentially damaging feedback mechanism where initial neurodegeneration, a core feature of PD, prompts microglia to release more of the very protein that facilitates alpha-synuclein uptake. Using an alpha-synuclein fibril-seeded model of PD, the study confirmed that GPNMB secreted by iMicroglia enhanced both the uptake of alpha-synuclein by neurons and the subsequent development of intracellular alpha-synuclein pathology. This effect was observed even in neurons genetically engineered to lack their own GPNMB (GPNMB knockout neurons), confirming that the GPNMB secreted from microglia is sufficient to drive pathology in recipient neurons.
Clinical Relevance: Human Data and Therapeutic Implications
The study's findings are strongly supported by human data, bridging the gap from cell culture models to clinical pathology. An analysis of 1,675 human postmortem brain samples established a direct link between GPNMB genetics and disease burden. The data showed that GPNMB genotypes that confer higher GPNMB expression were associated with more widespread alpha-synuclein pathology. This genetic evidence from a large human cohort reinforces the conclusion that GPNMB is a significant contributor to PD progression in patients. From a therapeutic standpoint, the study demonstrated that anti-GPNMB antibodies can rescue neurons from developing alpha-synuclein pathology in their experimental model. These results collectively suggest a self-amplifying cycle in PD: neurodegeneration triggers microglia to secrete more GPNMB, which in turn accelerates neuronal alpha-synuclein pathology and leads to further neurodegeneration. The authors propose that this cycle can be therapeutically interrupted, positioning anti-GPNMB antibodies as a potential disease-modifying strategy to slow the spread of pathology in Parkinson's disease.
References
1. Xicoy H, Wieringa B, Martens GJ. The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Molecular Neurodegeneration. 2017. doi:10.1186/s13024-017-0149-0
2. Guo J, Huang X, Dou L, et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduction and Targeted Therapy. 2022. doi:10.1038/s41392-022-01251-0
3. Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimer s & Dementia. 2012. doi:10.1016/j.jalz.2011.10.007
4. Piredda R, Desmarais P, Masellis M, Gasca-Salas C. Cognitive and psychiatric symptoms in genetically determined Parkinson's disease: a systematic review.. European journal of neurology. 2020. doi:10.1111/ene.14115
5. Pedersen CC, Maple-Grødem J, Lange J. A systematic review of biofluid phosphorylated α-synuclein in Parkinson's disease.. Parkinsonism & Related Disorders. 2024. doi:10.1016/j.parkreldis.2024.107240
6. Malek N, Swallow D, Grosset KA, Anichtchik O, Spillantini M, Grosset DG. Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson's disease - a systematic review.. Acta neurologica Scandinavica. 2014. doi:10.1111/ane.12247
7. Gao C, Jiang J, Tan Y, Chen S. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduction and Targeted Therapy. 2023. doi:10.1038/s41392-023-01588-0
8. Zhang W, Xiao D, Mao Q, Xia H. Role of neuroinflammation in neurodegeneration development. Signal Transduction and Targeted Therapy. 2023. doi:10.1038/s41392-023-01486-5
9. Kwon HS, Koh S. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational Neurodegeneration. 2020. doi:10.1186/s40035-020-00221-2
10. Colonna M, Butovsky O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annual Review of Immunology. 2017. doi:10.1146/annurev-immunol-051116-052358